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Journal article
BTK inhibitors synergise with 5-FU to treat drug-resistant TP53-null colon cancers
The Journal of pathology, v 250(2), pp 134-147
01 Feb 2020
PMID: 31518438
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Colorectal cancer (CRC) is the fourth cause of death from cancer worldwide mainly due to the high incidence of drug-resistance. During a screen for new actionable targets in drug-resistant tumours we recently identified p65BTK - a novel oncogenic isoform of Bruton's tyrosine kinase. Studying three different cohorts of patients here we show that p65BTK expression correlates with histotype and cancer progression. Using drug-resistant TP53-null colon cancer cells as a model we demonstrated that p65BTK silencing or chemical inhibition overcame the 5-fluorouracil resistance of CRC cell lines and patient-derived organoids and significantly reduced the growth of xenografted tumours. Mechanistically, we show that blocking p65BTK in drug-resistant cells abolished a 5-FU-elicited TGFB1 protective response and triggered E2F-dependent apoptosis. Taken together, our data demonstrated that targeting p65BTK restores the apoptotic response to chemotherapy of drug-resistant CRCs and gives a proof-of-concept for suggesting the use of BTK inhibitors in combination with 5-FU as a novel therapeutic approach in CRC patients. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Details
- Title
- BTK inhibitors synergise with 5-FU to treat drug-resistant TP53-null colon cancers
- Creators
- Marialuisa Lavitrano - Univ Milano Bicocca, Sch Med & Surg, Monza, ItalyLeonarda Ianzano - University of Milano-BicoccaSara Bonomo - University of Milano-BicoccaAnnamaria Cialdella - University of Milano-BicoccaMaria Grazia Cerrito - University of Milano-BicoccaFabio Pisano - University of Milano-BicoccaCarola Missaglia - University of Milano-BicoccaRoberto Giovannoni - Univ Milano Bicocca, Sch Med & Surg, Monza, ItalyGabriele Romano - Drexel University, Pharmacology and PhysiologyChelsea M. McLean - Janssen (Netherlands)Emile E. Voest - The Netherlands Cancer InstituteFilomena D'Amato - University of CagliariBarbara Noli - University of CagliariGian Luca Ferri - University of CagliariMarco Agostini - University of PaduaSalvatore Pucciarelli - University of PaduaKristian Helin - Memorial Sloan Kettering Cancer CenterBiagio E. Leone - University of Milano-BicoccaVincenzo Canzonieri - Centro di Riferimento OncologicoEmanuela Grassilli - University of Milano-Bicocca
- Publication Details
- The Journal of pathology, v 250(2), pp 134-147
- Publisher
- Wiley
- Number of pages
- 14
- Grant note
- RF-2010-2305526 / Italian Ministry of Health; Ministry of Health, Italy PON01_02782 / Italian Ministry of University and Research (MIUR); Ministry of Education, Universities and Research (MIUR) 2014-ATE-0374; 2015-ATE-0447; 2016-ATE-0299 / University of Milano-Bicocca FAR grants
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000499802100001
- Scopus ID
- 2-s2.0-85076103082
- Other Identifier
- 991021965770704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Oncology
- Pathology